Difluoromethyl ornithine protects against the neurotoxic effects of intrastriatally administered N-methyl-D-aspartate in vivo.

The neurotoxic effects of intrastriatally administered N-methyl-D-aspartate (NMDA) (250 nmol), as measured by reductions in striatal choline acetyl transferase activity and by increased binding of the glial marker [3H]PK 11195 10 days later, were reduced by coinfusion of the irreversible ornithine decarboxylase inhibitor difluoromethylornithine (250 nmol) in the rat. The data suggest a crucial role for the polyamines in NMDA receptor-mediated neurotoxicity.

The psychopharmacology of GABA synapses: update 1989.

Recent advances in the psychopharmacology of GABA synapses are reviewed. The usefulness of GABA mimetics in tardive dyskinesia and epilepsy has been confirmed, as has a dysfunction of GABA synapses in the etiopathology of these conditions. The antidepressant profile of GABA agonists in animal models for depression has been extended. The role of GABA receptors in the mechanism of action of antidepressants has been further delineated, with a parallelism occurring between the behavioral and biochemical response to antidepressant drug treatment in different animal models of depression.

The gabaergic hypothesis of depression.

UNLABELLED: 1. GABAergic mechanisms have been generally ignored in the study of mood disorders and antidepressant drug (AD) action. Recently data have accumulated indicating that GABAergic mechanisms may be involved in both of these. 2. Mood disorders: GABA levels are reported to be low in the CSF and plasma of depressed patients and are related to mood changes. GABAB receptors are decreased in the frontal cortex in two rodent behavioral models of depression and GABA release is reported diminished in the hippocampus. GABAergic drugs (progabide, fengabine) reverse the behavioral deficits in the rodent models and exert clear therapeutic effects in depressed patients. 3. AD action: In behavioral models imipramine upregulates GABAB receptors only in those animals which respond behaviorally to the AD. In naive rats repeated administration of varied ADs upregulates GABAB receptors in the frontal cortex whereas non-ADs (including amphetamine) do not. Bicuculline inhibits the action of imipramine in the learned helplessness model. GABAA receptor stimulation enhances noradrenaline release in the ventral NA pathway. 4. CONCLUSIONS: GABAergic mechanisms likely play a role in the modulation of mood and increasing GABAergic tone exerts and antidepressant effect. Actions at GABA synapses appear to be a fundamental facet of ADs, perhaps together with beta-adrenoceptor mediated events.

Selective antagonists of dopamine receptor subtypes differentially affect substance P levels in the striatum and substantia nigra.

Repeated administration to rats of SCH 23390, a specific antagonist of the D-1 dopamine receptor, produced an increase in the substance P immunoreactivity in the striatum but not in the substantia nigra, whereas similar treatment with sulpiride, a specific D-2 dopamine receptor antagonist, reduced the nigral but not the striatal content of the peptide. When the two antagonists were given together, the SCH 23390-induced increase in striatal substance P was significantly reduced. The SCH 23390-induced increase in striatal substance P was curtailed by concomitant administration of progabide, a selective gamma-aminobutyric acid (GABA) receptor agonist. These results suggest the existence in the nigro-striatal complex of two different substance P-containing neurons which are differentially regulated by the dopamine receptor subtypes and indicate a role of GABA in the action of SCH 23390.

Fengabine, a novel antidepressant GABAergic agent. II. Effect on cerebral noradrenergic, serotonergic and GABAergic transmission in the rat.

The effects of fengabine (a novel benzylidene derivative possessing clinically demonstrated antidepressant action) on neurochemical parameters related to norepinephrine, serotonin and gamma-aminobutyric acid (GABA) neurons have been investigated in the rat and mouse brain. When given acutely, fengabine (50-1000 mg/kg i.p.) does not alter norepinephrine uptake but accelerates the turnover rate of norepinephrine in the rat brain as demonstrated by the enhancement of: the alpha-methyl-p-tyrosine-induced disappearance of norepinephrine in the hypothalamus; 3,4-dihydroxyphenylacetic acid levels in noradrenergic cell body areas; the pargyline-induced accumulation of normetanephrine in the hypothalamus; and 3,4-dihydroxyphenylethyleneglycol levels in the hypothalamus, septum and spinal cord. No tolerance to the effect of fengabine on the latter biochemical parameter was observed after repeated treatment for 2 weeks at doses of 100 or 200 mg/kg i.p., b.i.d. Fengabine (100 or 200 mg/kg i.p., b.i.d.), given for 14 days, causes a desensitization of isoprenaline-stimulated adenylate cyclase in septal and cortical slices of the rat but fails to modify cortical beta, alpha-1 or alpha-2 adrenoceptor binding sites. Fengabine (up to 400 mg/kg i.p.) has no effect on rat cerebral serotonin uptake, synthesis or metabolism. Moreover, when given subacutely (100 or 200 mg/kg i.p., b.i.d. for 2 weeks), it fails to alter rat cortical serotonine receptors or [3H]imipramine binding sites. Fengabine (up to 50-100 microM) is also inactive in vitro on [3H] GABA binding to GABAA or GABAB receptors in the rat brain or on GABA transaminase activity in the mouse brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Fengabine, a novel antidepressant GABAergic agent. I. Activity in models for antidepressant drugs and psychopharmacological profile.

Fengabine (SL 79.229) is a novel benzylidene derivative with clinically proven antidepressant action. Fengabine is active in behavioral models for antidepressant drug action, reversing the passive avoidance deficit in olfactory bulbectomized rats, antagonizing the escape deficit in the learned helplessness model and decreasing paradoxical sleep in the rat. In contrast to tricyclic antidepressants, fengabine antagonizes 5-hydroxytryptophan-induced head twitches and only weakly reverses reserpine-induced ptosis. Fengabine inhibits neither monoamine uptake nor monoamine oxidase. A GABAergic mechanism of fengabine is indicated as bicuculline reverses its action in the olfactory bulbectomy and learned helplessness models. The wide-spectrum anticonvulsant action of fengabine is consistent with a GABA-mimetic action and is in contrast to the proconvulsant effect of most classical antidepressants.

GABA and affective disorders.

Recently sufficient evidence has accumulated to propose that a central GABAergic dysfunction may be primarily related to the pathology of affective disorders and that antidepressant mechanisms (pharmacological or electroconvulsive therapy, ECT) have an intrinsic GABAergic component. In depressed patients GABA levels are reported to be low in the CSF and plasma, and GABA synthesis is decreased in some brain areas, including the frontal cortex. GABAmimetics such as progabide and fengabine exert a therapeutic effect in depression. In behavioural laboratory models GABAmimetics exhibit antidepressant-like actions in the olfactory bulbectomized rat and in rats submitted to an inescapable shock (learned helplessness). Furthermore, antidepressant GABAmimetics decrease paradoxical sleep. In the olfactory bulbectomized rat, GABAB receptors are downregulated in the frontal cortex and in the learned helplessness model, GABA release is diminished in the hippocampus. These decreases are reversed by antidepressants in parallel with their behavioural activities. An intrinsic activity of widely varied antidepressants and ECT is the upregulation of GABAB receptors in the frontal cortex. This, together with the downregulation of beta-adrenergic receptors induced by these compounds, and the GABAB modulation of the beta-adrenergic second messenger system, strongly suggest that both GABAergic and beta-adrenergic responses are inherent to an antidepressant effect.

GABA receptor agonists and extrapyramidal motor function: therapeutic implications for Parkinson's disease.

GABA receptor agonists display a dual action on DA-mediated events. One includes a decrease in DA release, reduction in DA receptor density, and decreased response of postsynaptic cells to dopaminergic stimulation; it results in antidopaminergic effects. The other consists of a reduction of striatal cholinergic activity resulting in a facilitation of dopaminergic effects. These two effects could be dissociated depending on the dose of GABA receptor agonists. This dual action probably explains the results of clinical trials showing either amelioration of parkinsonian symptoms with aggravation of L-DOPA-induced dyskinesia or improvement of dyskinesia without or with aggravation of parkinsonian symptoms.

Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects.

Zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide hemitartrate] is reported to be a rapid onset, short duration hypnotic that interacts at the benzodiazepine recognition site. The present report establishes the neuropsychopharmacological profile of zolpidem and compares it with those of benzodiazepine hypnotics. Although in mice the effects of zolpidem are qualitatively similar to those of midazolam, triazolam and flunitrazepam, sedation with zolpidem occurs at doses 10 and 20 times lower than those inducing anticonvulsant and myorelaxant effects, respectively. In contrast, the benzodiazepines studied induce sedation at doses causing myorelaxation and which are 2 to 6 times superior to those antagonizing pentetrazole-induced convulsions. In the rat, zolpidem induces sleep (as indicated behaviorally and electrocorticographically) and displays anticonflict activity in a punished drinking paradigm, as do the benzodiazepines. However, whereas benzodiazepine hypnotics induce EEG sleep patterns in curarized rats at doses similar or inferior to those active in the conflict test (in freely moving animals), the hypnotic effect of zolpidem is seen at doses 10 times lower than those producing an anticonflict effect. Moreover, a qualitative difference between the effects of zolpidem and benzodiazepines is observed in electrocorticographic recordings obtained in curarized rats: electrocorticographic hypersynchronization induced by zolpidem is dominated by the energy increase within the 2 to 4 Hz band whereas the benzodiazepines increase predominantly energy levels within the 12 to 14 Hz band. Studies of the sleep-wakefulness cycle in the rat and the cat revealed that hypnotic doses of zolpidem do not alter the pattern of physiological sleep, although elevated doses of the drug decrease paradoxical sleep and increase slow wave sleep. In rats trained to discriminate chlordiazepoxide, zolpidem fails to generalize with the chlordiazepoxide-associated lever indicating that the compound and benzodiazepines do not share the same discriminative stimulus properties. Nevertheless, the anticonvulsant, hypnotic, myorelaxant and anticonflict effects of zolpidem are antagonized by benzodiazepine receptor antagonist Ro 15-1788 and CGS 8216 indicating an involvement of the benzodiazepine recognition site in the action of this drug. The highly selective sedative effect of zolpidem (as compared to myorelaxant and anticonvulsant effects) suggests that it may possess a specificity for certain subtypes of benzodiazepine receptors.

Non-benzodiazepine anxiolytics: potential activity of phenylpiperazines without 3H-diazepam displacing action.

Four phenylpiperazine derivatives exhibited an activity similar to benzodiazepines and meprobamate in the 4-plate test. One of these (compound IV) demonstrated anxiolytic like activity in a step-down avoidance technique, in electroshock induced aggression and in the staircase test. In contrast to benzodiazepines, compound IV was not anticonvulsant, myorelaxant or sedative. Confirmation of the anxiolytic activity of compound IV in animal models was obtained in 3 separate clinical trials in anxious patients. The mechanism of action of these phenylpiperazines appears to be different from the benzodiazepines as they do not displace 3H-diazepam binding nor do they interact with other elements of the GABA receptor macromolecular complex. Instead, compound IV interacts with both dopaminergic and serotoninergic neuron systems. Thus, from this data it would appear that an activity at the benzodiazepine recognition site is not obligatory for anxiolytic activity in man or in animals models.

Progabide reverses the nigral substance P reduction induced by chronic impairment of dopaminergic transmission.

Repeated treatment with haloperidol or lesion of nigrostriatal dopaminergic neurons with 6-hydroxydopamine produced a reduction in substance P immunoreactivity in the rat substantia nigra. This reduction was reversed by the repeated administration of progabide, a selective GABA receptor agonist. As GABA inhibits substance P release, these results suggest that the reduction in nigral substance P levels was due to an increased liberation of the peptide probably related to deficient GABAergic function induced by impairment of striatal dopaminergic transmission.

GABA receptor agonists: pharmacological spectrum and therapeutic actions.

From the data discussed in this review it appears that GABA receptor agonists exhibit a variety of actions in the central nervous system, some of which are therapeutically useful (Table V). GABA receptor agonists, by changing the firing rate of the corresponding neurons accelerate noradrenaline turnover without changes in postsynaptic receptor density and diminish serotonin liberation with an up-regulation of 5HT2 receptors. These effects differ from those of tricyclic antidepressants which primarily block monoamine re-uptake and cause down-regulation of beta-adrenergic and 5HT2 receptors. The GABA receptor agonist progabide has been shown to exert an antidepressant action which is indistinguishable from that of imipramine in patients with major affective disorders. The fact that: (a) GABA receptor agonists and tricyclic antidepressants affect noradrenergic and serotonergic transmission differently; and (b) tricyclic antidepressants alter GABA-related parameters challenges the classical monoamine hypothesis of depression and suggests that GABA-mediated mechanisms play a role in mood disorders. Decreases in cellular excitability produced by GABAergic stimulation leads to control of seizures in practically all animal models of epilepsy. GABA receptor agonists have a wide spectrum as they antagonize not only seizures which are dependent on decreased GABA synaptic activity but also convulsant states which are apparently independent of alterations in GABA-mediated events. These results in animals are confirmed in a wide range of human epileptic syndromes. GABA receptor agonists decrease dopamine turnover in the basal ganglia and antagonize neuroleptic-induced increase in dopamine release. On repeated treatment, progabide prevents or reverses the neuroleptic-induced up-regulation of dopamine receptors in the rat striatum and antagonizes the concomitant supersensitivity to dopaminomimetics. Behaviorally, GABA receptor agonists diminish the stereotypies induced by apomorphine or L-DOPA suggesting that GABAergic stimulation results also in an antidopaminergic action which is exerted beyond the dopamine synapse. These effects of GABA receptor agonists may represent the basis of the antidyskinetic action of these compounds which, however, remains to be fully confirmed. GABA receptor agonists reduce striatal acetylcholine turnover, an effect which occurs at doses much lower than those which affect dopamine neurons. Since hyperactivity of cholinergic neurons plays a determinant role in the pathogenesis of some parkinsonian symptoms, it is conceivable that GABAergic stimulation is effective in ameliorating Parkinson's disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of GABA mimetics and lithium on biochemical manifestations of striatal dopamine target cell hypersensitivity.

The potential mechanisms whereby GABA mimetics and the antimanic agent lithium stabilize dopaminergic transmission are discussed. Evidence is presented that GABA mimetics, and in particular progabide, affect dopamine-mediated events in the basal ganglia on at least three levels. First, they reduce dopamine neuron activity in both the basal and the activated states. Secondly, on a long-term basis, they antagonize the proliferation of striatal dopamine receptors subsequent to chronic neuroleptic treatment. Thirdly, they modulate the expression of dopamine receptor activation by acting distally to the dopaminergic synapse. Lithium and GABA mimetics have the last two properties in common. These effects may represent the biochemical basis for the therapeutic action of GABA mimetics in iatrogenic dyskinesias. Moreover, the similarity between the biochemical effects of GABA mimetics and lithium suggest that the former drugs may have a therapeutic potential in mania.

Involvement of the D-2 dopamine receptor in the neuroleptic-induced decrease in nigral substance P.

Repeated treatment with, but not single administration of drugs which impair dopaminergic transmission produced a consistent reduction in substance P immunoreactivity in the rat substantia nigra. This effect appears to be related to the D-2 dopamine receptor function as the blockade of this receptor subtype by selective antagonists produced effects qualitatively similar to those produced by drugs lacking selectivity for different subclasses of dopamine receptors.

Experimental basis for the antidepressant action of the GABA receptor agonist progabide.

gamma-Aminobutyric acid (GABA) receptor agonists (e.g. progabide) are effective in behavioral tests predictive of antidepressant drug action. Also, these compounds, by changing the firing rate of the corresponding neurons, accelerate norepinephrine turnover (without changes in postsynaptic receptor density) and decrease 5-hydroxytryptamine (5-HT) liberation (with up-regulation of 5-HT2 receptors). At variance, tricyclic antidepressants block monoamine reuptake and cause down-regulation of beta-adrenergic and 5-HT2 receptors. Progabide exerts an antidepressant action which is indistinguishable from that of imipramine. The different modes of action of GABA receptor agonists and tricyclics, as well as alterations of GABA-related parameters by tricyclics, challenge the classical monoaminergic hypothesis of depression and suggest that GABA-mediated mechanisms play a role in this disorder.

Pharmacology of the GABAergic system: effects of progabide, a GABA receptor agonist.

Stimulation of GABA receptors (e.g. by progabide, a new GABA receptor antagonist, or by muscimol) enhances the liberation of norepinephrine in limbic forebrain areas of the rat and reduces 5-hydroxytryptamine turnover. On repeated administration, this latter effect is associated with an up-regulation of 5-HT2 receptors as it occurs after electroconvulsive shock. The monoaminergic changes induced by progabide, though dissimilar from those induced by tricyclics, are probably connected with the antidepressant action on the compound observed in double-blind clinical trials. In the basal ganglia, GABA receptor agonists reduce dopamine turnover and potentiate the cataleptogenic action of neuroleptics. They also antagonize the sterotypic behaviour induced by dopaminomimetics, indicating an additional action beyond the dopamine synapse. On repeated co-administration with neuroleptics, progabide antagonizes the tolerance to the cataleptogenic action, the supersensitivity to dopaminomimetics, and the increase in 3H-spiperone binding which are caused by sustained neuroleptic treatment. This appears to be the basis for the clinical action of progabide in neuroleptic-induced dyskinesia, L-dopa-induced involuntary movements, and possibly mania. GABA receptor agonists decrease cellular excitability in several animal models and antagonize seizures, whatever their origin (GABA-mediated or GABA unrelated mechanisms). Progabide has been shown to be effective in various forms of epilepsy in double-blind and long-term clinical trials. The compound exerts a therapeutic action in patients resistant to "classical" antiepileptic drugs, in the virtual absence of major side effects.

The potential use of GABA agonists in psychiatric disorders: evidence from studies with progabide in animal models and clinical trials.

Progabide, a new antiepileptic GABA agonist of moderate affinity for GABA receptors, has been studied in a number of psychiatric disorders and the results compared with the action of this drug in animal models. In an animal model for anxiety (the aversive response to periaqueductal grey stimulation in the rat) progabide had a similar action to that of diazepam. However in clinical trials to date the effect of the GABA agonist was inferior to that of benzodiazepines. As progabide diminishes both the nigrostriatal dopamine neuron activity and the effects of striatal dopamine receptor activation, a trial in schizophrenic patients was undertaken. Progabide was devoid of any evident antipsychotic action. However a certain improvement in responsiveness to the environment and in social interactions was noticed in hebephrenic and schizoaffective syndromes. This lack of antipsychotic effect of progabide may be a reflection of the weak activity of GABA agonists on limbic dopamine neurons. In these various clinical trials a definite improvement of affect and mood was noted in those patients receiving progabide. In clinical trials in depressed patients progabide produces a significant reduction in depressive symptoms, an action similar to that of imipramine both for the global clinical rating and the HRSD. This antidepressant activity is reflected by the action of progabide in behavioural models of depression such as olfactory bulbectomy, learned helplessness and the sleep-wake cycle.

Pharmacological and therapeutic actions of GABA receptor agonists.

GABA receptor agonists, e.g. progabide, modify the activity of several brain neuronal systems which are implicated in the pathogenesis of some neuropsychiatric disorders. Thus, alterations in noradrenergic and serotoninergic transmissions induced by progabide may be a mechanism involved in the antidepressant action of this drug in the clinic. The antagonism of the neuroleptic-induced increase in dopamine receptor sensitivity and the decrease in dopamine synthesis and release may be responsible for the effectiveness of the GABA receptor agonists in the treatment of neuroleptic- and L-DOPA-induced dyskinesia. This action of GABA receptor agonists also suggests their therapeutic potential in mania. Finally, decrease in cellular excitability induced by GABA receptor agonists, e.g. progabide, accounts for their efficacy in epilepsy.